Project Summary Dopamine receptors are the primary therapeutic targets for a variety of neurological and psychiatric disorders, including schizophrenia, Parkinson's disease, and many other movement disorders. The five subtypes of dopamine receptors (D1-D5) are members of the superfamily of G protein-coupled receptors. This proposal is focused on the D2 receptor and, in particular, on the functional consequences of a novel DRD2 allelic variant that is linked to a movement disorder in at least one pedigree. The two Aims will test the hypotheses that the putatively pathogenic variant will exhibit altered signaling and cell surface expression compared to the reference D2 receptor when expressed in a neuronal cell line (Aim 1) or in dopamine neurons in mouse brain (Aim 2a), and that mice expressing the novel variant will exhibit motor impairments consistent with the human phenotype (Aim 2b). In Aim 1 we will determine if the impaired recruitment of arrestin and enhanced activation of G proteins observed when expressed in human embryonic kidney 293 cells is also characteristic of the novel variant when expressed in a neuronal cell line. In Aim 2 we will create a knock-in mouse model of homozygous and heterozygous expression of the putatively pathogenic variant. We will evaluate the functional properties of the novel variant in midbrain dopamine neurons using slice electrophysiology, and conduct analyses of behaviors that are thought to model the human clinical condition. In addition, D2 receptor expression will be quantified in midbrain and neostriatum of the knock-in mouse. The aims proposed here will quantify the effect of this novel polymorphism on the function and expression of the D2 receptor in neuronal cells and in mouse brain and should provide a biological explanation for manifestation of neurological dysfunction in humans with this variant.